Evaluation of severe adverse cutaneous drug reactions in patients admitted to tertiary care center: A cross‐sectional study

Abstract Background and Aims Adverse cutaneous drug reactions (ACDRs) are common and potentially life‐threatening, while also hindering patient compliance to medications. Given the regional differences in patterns and prevalence of ACDRs, it is important to study the epidemiology, as well as the clinical and outcome patterns of patients with ACDRs in Iran. Methods This cross‐sectional study on ACDRs was conducted among hospitalized patients in a referral university hospital in the city of Isfahan, Iran. The patients' demographics, clinical information, and outcomes, including age, gender, past medical history, medication history, drug reaction with eosinophilia and systemic symptoms (DRESS) diagnosis, Steven‐Johnson Syndrome (SJS) diagnosis, toxic epidermal necrosis (TEN) diagnosis, treatment regimen (steroids or intravenous immunoglobulin [IVIG]) and outcome information, including intensive care requirements, severe medical complications, or death, were obtained from medical records. Results A total of 195 patients with a mean age of 40 years and consisting of 61% females were included. Carbamazepine, lamotrigine, sodium valproate, and phenytoin are the most commonly reported medications. Rate of complications was 45% with DRESS, SJS, and TEN diagnosed in 26%, 47%, and 19%, respectively. Treatment was carried out with steroids and IVIG in 81% and 19%, respectively. Among patients, 15% required intensive care and 5% died. Diagnosis of TEN, older age, and baseline heart disease were predictors of mortality. Patients with SJS were younger and more likely to be males, and they were more likely to have eye complications. On the other hand, patients with the diagnosis of TEN were more likely to receive IVIG and intensive care, and had a higher mortality rate. Conclusion Our study provides insight into the demographics and clinical patterns of Iranian patients with ACDRs. This will help in predicting rates of complications, treatments, and outcomes in patients and therefore make proper management decisions.

Following excluding patients with over 50% missing information, 195 patients were included in the study.The patients' demographics, clinical information, and pathologic data were extracted from medical records.Those parameters included age, gender, past medical history, medication history, DRESS, SJS, and TEN diagnoses.A clinical diagnosis was made by dermatologist.In addition, treatment regimens (steroids or intravenous immunoglobulin [IVIG]) and outcome information, including intensive care requirements, severe medical complications, or death, were obtained from medical records.
Statistical analysis was performed using Stata Software.For descriptive analysis, data are demonstrated as mean ± standard deviation or percentage (total number).To compare data, independent sample T test and Mann-Whitney test were used for continuous variables.For categorical data, χ2 was used.p Values less than 0.05 were considered significant.

| RESULTS
Demographics, baseline clinical information, and clinical outcomes of the 195 included patients have been demonstrated in Table 1.The mean age of the patients was 39.5 (SD: 18.6; range: 1-88) years and 61% were female.Also, the median number of ACDR-causing medications T A B L E 1 Demographic and clinical characteristics of patients with skin reaction in a tertiary referral center in Isfahan, Iran.

| Impact of medications and past medical history on clinical and outcome profile of patients
Baseline clinical information and outcome characteristics have been tabulated in Table 4 based on the most common medications that the patients have been taking, which were known to cause ACDR.There was a markedly decreased rate of DRESS in patients taking metronidazole (8%) compared with other medications (18%−39%).On the other hand, metronidazole was associated with higher rate of SJS (75% compared with 39%-53%).Sodium valproate had the lowest association with TEN (7% vs. 15%-24%).There was also a notable increase in mortality in patients taking ciprofloxacin (15% vs. 0%-8%).
T A B L E 5 Clinical profile and outcomes of patients tabulated based on presence of severe complications, DRESS, SJS, or TEN.F I G U R E 1 A case of overlapping toxic epidermal necrosis and Steven-Johnson syndrome in a middle-aged male with lupus.

Variables
F I G U R E 2 A case epidermal detachment with above 30% involvement, along with mucosal lesions.We present clinical figures of patients in our study in Figures 1-3. Figure 1 presents a case of overlapping TEN and SJS in a middle-aged male with lupus.Figure 2 demonstrates a case of epidermal detachment (>30%) along with mucosal lesions.Figure 3 illustrates a case of SJS with mucous wounds, atypical target lesions, and epidermal detachment below 10% of the body.

| DISCUSSION
Adverse cutaneous reactions present in a spectrum including less severe immediate or delayed hypersensitivity reactions such as maculopapular exanthema, urticaria, and fixed drug reaction, to more rare but life-threatening reactions such as TEN, SJS DRESS. 18In this study, we reported epidemiological, clinical and outcome information for the more severe ACDR, including SJS, TEN, and DRESS.We observed that there are more females included in this cohort study, which is compatible with prior studies showing more prevalence of ACDRs in the female population. 16This has been attributed to higher consumption of medications and more elderly patients, both precipitating factors for ACDRs, in the female population.Since our study is not population-based and only involves patients admitted to a tertiary care center, we cannot comment on the community F I G U R E 3 A case of Steven-Johnson syndrome with mucous wounds, atypical target lesions, and epidermal detachment below 10% of the body.
prevalence of severe ACDRs, but we can confirm that in Iran, ACDRs are more prevalent among females.In our cohort, female patients are significantly older than males, confirming higher age in females as a potential explanation for gender discrepancies.Males were more likely to receive IVIG, possibly explained by higher prevalence of SJS in male patients.There was no outcome difference between male and female patients.
The average age of patients with ACDRs is 40 years, which is younger than reported in European countries, 19 and more similar to studies on the Asian population. 20This is most likely related to epidemiological and genetic similarities, but more studies are warranted to address age profile of patients with ACDRs.Age was highly associated with mortality (p < 0.001) with 6.5 times more mortality in the highest quantile compared with the lowest quantile.
There was lower rate of treatment with IVIG in elder people, which could be potentially explained by concerns over the side effect profile of IVIG for elderly.
The immune system changes with age from a mainly Th2 pathway to a Th1 pathway, which has led to the development of specific management guidelines in elderly patients. 21 We have antiepileptic medications to be the most common drug associated with ACDRs.Studies have shown while antibiotics and NSAIDS are the most commonly reported medications for all types of ACDRs, 14,19,23 when limiting analysis or more severe ACDRs such as SJS or TEN, antiepileptic drugs such as carbamazepine, phenytoin, and lamotrigine are most frequently associated. 24In our cohort, rates of SJS, TEN, and SJS are 47%, 19%, and 26%, respectively.Patients with SJS were younger and more likely to be males, and they were more likely to have eye complications.On the other hand, patients with the diagnosis of TEN were more likely to receive IVIG and intensive care, and had a higher mortality rate.
The majority of patients (81%) have been treated with oral steroids, while 19% were treated with IVIG.In our studied cohort, 15% of patients required intensive care, and a 5% mortality rate was reported.Besides heart disease being associated with higher mortality, there was an intriguing association between the diagnosis of autoimmune diseases and lower rates of SJS and TEN.Given the immune-mediated nature of SJS and TEN, 20 immunomodulatory medications for patients with the autoimmune disease may explain lower rate of TEN or SJS.A higher sample size is required to enable the multi-factorial analysis.
As mentioned, the limitations of our study included the small sample size and single-center nature of our study, along with the retrospective design.Another limitation was the lack of laboratory evaluation, including C3, C4 C1INH, while also the documentation of SCORETEN among our patients.However, our results show the significance of ACDRs in our country while also providing valuable information for future multicentral and meta-analytic studies.

| CONCLUSION
We

| 3 of 9 T A B L E 4
Abbreviations: DRESS, drug reaction with eosinophilia and systemic symptoms; IVIG, intravenous immunoglobulin; SJS, Steven-Johnson syndrome; TEN, toxic epidermal necrosis.
An examination of cytokines in the peripheral blood of patients with IgEmediated allergic atopic dermatitis, conducted by Bozek et al., demonstrated a Th2 cytokine profile, predominantly featuring interleukin (IL)-4, IL-5, and IL-13 in both young and elderly individuals.In contrast, elderly patients with low total IgE levels typically display a Th1 cytokine profile, characterized by elevated levels of IL-17. 22 Clinical profile and outcomes of patients demonstrated by gender.Clinical profile and outcomes of patients demonstrated by age.
T A B L E 2Abbreviations: DRESS, drug reaction with eosinophilia and systemic symptoms; IVIG, intravenous immunoglobulin; SJS, Steven-Johnson syndrome; TEN, toxic epidermal necrosis.MOSHAYEDI ET AL.
have shown that the demographic patterns of patients with ACDRs are similar to other reports from Asian countries.Mortality was around 5% and it was associated with diagnosis of TEN, older age, and baseline heart disease.In this report, we have evaluated demographic, clinical patterns, and outcome information in patients admitted to a referral center for ACDRs.This will help in understanding the clinical patterns of patients with ACDRs in Iran and help in predicting rates of complications, treatments, and outcomes in patients.